According to World Health Organization, the total number of patients with cancer in all the countries in the world amounts to about thirty seven millions. At the final stage of cancer, about 80 to 90% of patients suffer from a pain, though the degree of the pain varies from case to case. In terminal cancer, various social and mental distresses make the physical pain further intolerable. Accordingly, it is highly meaningful not only for the patient himself or herself but also for his or her family members to ease the pain to thereby have a humane time at the end of the life.
The final means for relieving the cancerous pain is the administration of morphine. However there is some hesitation in using morphine since it is a narcotic. Thus it has been required to develop a non-narcotic analgesic with a potent efficacy. Under these circumstances, there have been developed buprenorphine hydrochloride and/or buprenorphine (hereinafter called "buprenorphine (hydrochloride)" in some cases). Buprenorphine (hydrochloride) is a non-narcotic analgesic which has an analgesic efficacy about 30 times higher than that of morphine and is used in the form of injections, sublingual tablets and suppositories in order to relieve cancerous pain and postoperative pain.
However buprenorphine provides no solution to the serious problems accompanying the administration of opium analgesics, e.g., the addictiveness and a low bioavailability (BA) achieved in oral administration. For example, the gastrointestinal BA of buprenorphine is only about 10%, while its sublingual BA is only about 50%. That is to say, buprenorphine should be orally administered in a dose about 10 times more than the dose in the case of intravenous administration, which indicates that the use of buprenorphine suffers from a serious problem. This is because respiratory depression caused by the excessive administration of buprenorphine cannot be treated with an antagonist, e.g., nalorphine which is an antidote suitable for opiate intoxication.
On the other hand, injections should be administered in general by physicians or nurses, which makes domiciliary treatment difficult. Also, injections exhibit only a short duration and thus should be administered at short intervals. These characteristics interfere with the emergent treatment for acute pain. Also, suppositories have a disadvantage of a short duration.
On the other hand, percutaneous administration, which has been vigorously studied recently, has a number of advantages as will be described below. (1) It is expected that the percutaneous administration achieves a drug effect lasting for 24 hours or longer, which makes such frequent administration unnecessary as required in the cases of injections, sublingual tablets and suppositories. (2) It is expected that the percutaneous administration makes absorption uniform and thus excessive administration can be avoided. Therefore side effects can be relieved. (3) The percutaneous administration causes neither any unevenness in the absorption/retention in the digestive tracts nor first pass effect in the liver. (4) The percutaneous administration is applicable even to a patient for whom oral administration is impossible.
However, drugs are generally poor in percutaneous absorption and thus can be hardly absorbed in a required dose at a practically available adhesion area, i.e., 100 cm.sup.2 or less. This is seemingly because the horny layer of the skin serves as a barrier. Buprenorphine (hydrochloride) is not an exception but shows extremely poor percutaneous absorption. Therefore attempts have been made to develop a percutaneous absorption preparation of buprenorphine (hydrochloride) which has many advantages as described above (for example, JP-A-2-191214, JP-A-2-191215, JP-A-2-237915, JP-A-3-163014, JP-A-3-193732, JP-A-4-217926, U.S. Pat. No. 5,069,909; the term "JP-A" as used herein means an "unexamined published Japanese patent application"). However most of these patents are not usable in practice, since the skin penetration of a drug is discussed in the form of a solution or a penetration enhancer is merely added to a pressure-sensitive adhesive without any special idea and thus a percutaneous absorption preparation can be hardly formed thereby. In addition, penetration enhancers comprising organic acids, which might induce skin irritation, are employed in some of these patents. Thus they involve some problems from the viewpoint of safety.
When a percutaneous penetration enhancer is added in order to improve the percutaneous absorption of buprenorphine (hydrochloride), the penetration enhancer sometimes oozes out to the surface of a plaster thus changing the properties of the preparation. Further, the addition of a plasticizer or a penetration enhancer to the pressure-sensitive adhesive causes a decrease in the cohesive force and, as a result, the pressure-sensitive adhesive remains on the skin surface. To solve this problem, attempts have been made to add silicic acid anhydride (hydrophilic silicic anhydride, hydrophobic silicic anhydride) to thereby enhance the cohesive force (JP-A-3-291218, JP-A-4-299927, JP-A-4-312525). However the addition of silicic anhydride results in a problem that the thixotropic properties of the plaster solution thus elevated interfere with application.
The present invention, which has been completed in order to solve the above-mentioned problems, aims at providing a percutaneous absorption preparation with excellent skin penetration of buprenorphine (hydrochloride). The present invention also aims at providing a percutaneous absorption preparation having excellent skin penetration of buprenorphine (hydrochloride) and an excellent storage stability.
The present inventors have conducted extensive studies in order to solve the above-mentioned problems. As a result, they have found out that the skin penetration of buprenorphine (hydrochloride) can be synergistically elevated by using a combination of a monoglyceride of a fatty acid having 6 to 8 carbon atoms and isopropyl myristate as a penetration enhancer, thus completing the present invention.